Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][I:2].[CH3:3][N:4]([CH2:6][C:7]1[C:11]2[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][C:10]=2[NH:9][CH:8]=1)[CH3:5]>C1C=CC=CC=1>[I-:2].[CH2:17]([O:16][C:14]1[CH:15]=[C:10]2[C:11]([C:7]([CH2:6][N+:4]([CH3:1])([CH3:3])[CH3:5])=[CH:8][NH:9]2)=[CH:12][CH:13]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CN(C)Cc1c[nH]c2cc(OCc3ccccc3)ccc12
Reactant: CI
Solvent: c1ccccc1
Product: C[N+](C)(C)Cc1c[nH]c2cc(OCc3ccccc3)ccc12
Product: [I-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methyl iodide (15 mL) was added to a stirred mixture of 6-benzyloxygramine (10 g, 35.66 mmol) in dry benzene (150 mL) at ambient temperature. The mixture was stirred at ambient temperature for 30 minutes, then allowed to stand in the dark overnight. The solid was collected by filtration, then dried in high vacuum to give (6-benzyloxy-1H-indol-3-ylmethyl)trimethylammonium iodide (17.5 g).
Reaction SMILES: [C:1]([O:4][C@H:5]([C@H:8]1[O:12][C@@H:11]([N:13]2[C:17]3[N:18]=[C:19]([NH2:23])[NH:20][C:21](=[O:22])[C:16]=3[S:15][C:14]2=[O:24])[C@@H:10](CC([O-])=O)[CH2:9]1)[CH2:6][CH3:7])(=[O:3])[CH3:2].C([O-])([O-])=[O:30].[K+].[K+].CC(O)=O>CO>[NH2:23][C:19]1[NH:20][C:21](=[O:22])[C:16]2[S:15][C:14](=[O:24])[N:13]([C@@H:11]3[O:12][C@H:8]([C@@H:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:6][CH3:7])[CH2:9][C@H:10]3[OH:30])[C:17]=2[N:18]=1
Reactant: O=C([O-])[O-]
Reactant: CC[C@H](OC(C)=O)[C@@H]1C[C@H](CC(=O)[O-])[C@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)O1
Agent: [K+]
Solvent: CC(=O)O
Solvent: CO
Product: CC[C@H](OC(C)=O)[C@@H]1C[C@@H](O)[C@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)O1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 36 %

Procedure:
To a solution of [(2R,3R,5S)-5-[(1S)-1-acetoxypropyl]-2-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)tetrahydrofuran-3-yl]acetate (compound 6h, 210 mg, 0.5 mmol) in methanol (25 mL) was added K2CO3 (136 mg, 1 mmol). After being stirred at room temperature for 10 min, the reaction was adjusted to pH 7.0 by addition of HOAc (120 mg, 2 mmol), concentrated in vacuo and the residue was purified by preparative HPLC to afford 66.7 mg of [(1S)-1-[(2S,4R,5R)-5-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)-4-hydroxy-tetrahydrofuran-2-yl]propyl]acetate (Example 6) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[C@@H:6]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:5][CH2:4][N:3]1[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(N(C(C)C)C(C)C)C.Cl[C:31]1[C:36]([Cl:37])=[CH:35][C:34]([C:38]([F:41])([F:40])[F:39])=[CH:33][N:32]=1>CN(C=O)C.CCOC(C)=O>[Cl:37][C:36]1[C:31]([N:18]2[CH2:17][CH2:16][CH:15]([N:3]3[CH2:4][CH2:5][C@H:6]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:2]3=[O:1])[CH2:20][CH2:19]2)=[N:32][CH:33]=[C:34]([C:38]([F:40])([F:39])[F:41])[CH:35]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C2CCNCC2)C1=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C2CCN(c3ncc(C(F)(F)F)cc3Cl)CC2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.7 %

Procedure:
To a solution of (S)-tert-butyl 2-oxo-1-(piperidin-4-yl)pyrrolidin-3-ylcarbamate (4.0 g, 14 mmol) in DMF (50 mL) was added N-ethyl-N-isopropylpropan-2-amine (5.5 g, 42 mmol) and 2,3-dichloro-5-(trifluoromethyl)pyridine (9.1 g, 42 mmol) and the reaction was stirred overnight at ambient temperature. The reaction was diluted with EtOAc (about 200 mL) and the organic layer was washed with water (100 mL), and brine (50 mL), dried over MgSO4, and concentrated under vacuum. The crude material was purified on silica using a gradient of DCM to 5% EtOAc/DCM as eluent to give (S)-tert-butyl 1-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-ylcarbamate (4.0 g, 61%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]2[CH2:19][CH2:20][CH2:21][S:22]([O:25]C2C(F)=C(F)C(F)=C(F)C=2F)(=O)=[O:23])(=[O:12])=[O:11])=[C:5]([CH3:37])[CH:4]=1.[CH3:38][N:39]1[CH2:44][CH2:43][CH:42]([N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:41][CH2:40]1.N12CCCN=C1CCCCC2.C(=O)(O)[O-].[Na+]>O1CCCC1.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:37])[C:6]([S:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]2[CH2:19][CH2:20][CH2:21][S:22]([N:48]2[CH2:47][CH2:46][N:45]([CH:42]3[CH2:43][CH2:44][N:39]([CH3:38])[CH2:40][CH2:41]3)[CH2:50][CH2:49]2)(=[O:23])=[O:25])(=[O:11])=[O:12])=[C:7]([CH3:9])[CH:8]=1
Reactant: COc1cc(C)c(S(=O)(=O)N2CCCCC2CCCS(=O)(=O)Oc2c(F)c(F)c(F)c(F)c2F)c(C)c1
Reactant: CN1CCC(N2CCNCC2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1cc(C)c(S(=O)(=O)N2CCCCC2CCCS(=O)(=O)N2CCN(C3CCN(C)CC3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Perfluorophenyl 3-(1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)propane-1-sulfonate (40 mg, 0.07 mmol) and 1-(1-methyl-4-piperidinyl)piperazine (25 mg, 0.14 mmol) were dissolved in tetrahydrofuran (10 ml), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.03 ml, 0.21 mmol) was added under an inert gas and the mixture was refluxed for 1 h and stirred at room temperature for 15 h. Methylene chloride and saturated sodium bicarbonate solution (10 ml of each) were added, the phases were separated and the aqueous phases were extracted with methylene chloride (20 ml). The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) with ethyl acetate/methanol/ammonia (25 aq) (200:100:1). Yield: 18 mg (45%). MS, m/z=571.3 [MH]+
Reaction SMILES: F[C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[C:9]1C=C(CO)C(=O)N(CC(C)C)N=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:30]=[C:31]([C:36]([O:38][CH3:39])=[O:37])[C:32](=[O:35])[NH:33][N:34]=2)=[CH:25][C:24]=1[CH3:40].C(Cl)C1C=CC=CC=1>>[CH2:9]([N:33]1[C:32](=[O:35])[C:31]([C:36]([O:38][CH3:39])=[O:37])=[CH:30][C:29]([C:26]2[CH:27]=[CH:28][C:23]([F:22])=[C:24]([CH3:40])[CH:25]=2)=[N:34]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1
Reactant: CC(C)Cn1nc(-c2ccc(F)cc2F)cc(CO)c1=O
Reactant: COC(=O)c1cc(-c2ccc(F)c(C)c2)n[nH]c1=O
Solvent: ClCc1ccccc1
Product: COC(=O)c1cc(-c2ccc(F)c(C)c2)nn(Cc2ccccc2)c1=O
Yield: 71 %

Procedure:
Following the procedure of Example 1 (6), 6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and benzyl chloride were reacted to yield the title compound as yellow needles (yield: 71.0%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:5]([CH:14]=[N:15][OH:16])[C:4]([CH3:17])=[N:3]1.[H-].[Na+].Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2([CH3:33])[O:32][CH2:31][CH2:30][O:29]2)=[CH:24][CH:23]=1.O>O1CCOCC1>[CH3:33][C:28]1([C:25]2[CH:26]=[CH:27][C:22]([CH2:21][O:16][N:15]=[CH:14][C:5]3[C:4]([CH3:17])=[N:3][N:2]([CH3:1])[C:6]=3[O:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:23][CH:24]=2)[O:29][CH2:30][CH2:31][O:32]1
Reactant: Cc1nn(C)c(Oc2ccccc2)c1C=NO
Reactant: CC1(c2ccc(CBr)cc2)OCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nn(C)c(Oc2ccccc2)c1C=NOCc1ccc(C2(C)OCCO2)cc1
Yield: 74.2 %

Procedure:
1.0 Gram (0.0043 mole) of 1,3-dimethyl-5-phenoxypyrazole-4-carbaldehyde oxime was dissolved in 20 ml of dioxane, and 0.14 g (0.0058 mole) of sodium hydride was added. Thereafter, 1.1 g (0.0043 mole) of 2-(4-bromomethylphenyl)-2-methyl-1,3-dioxolane was added to this solution which was then heated under reflux for 3 hours. After completion of the reaction, the reaction solution was poured into 200 ml of cold water and extracted with ethyl acetate. The ethyl acetate extract was washed with water and dried, and ethyl acetate was removed by evaporation to obtain an oily product. This oily product was column-chromatographed on silica gel to obtain 1.3 g of the desired compound.
Reaction SMILES: [C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([S:18][C:19](=O)C)=[C:14]([F:22])[CH:13]=2)[CH2:7]1)(=[O:3])[CH3:2].CI>CN1CCCC1=O>[C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[C:14]([F:22])[CH:13]=2)[CH2:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(SC(C)=O)c(F)c2)C(=O)O1
Solvent: CI
Solvent: CN1CCCC1=O
Product: CSc1ccc(N2C[C@H](CNC(C)=O)OC2=O)cc1F
Reaction time: 8 h

Procedure:
Prepared according to Method A of the General Procedures for Preparation of 5-(S)-(N-Acylaminomethyl)-3-[4′-(substituted)thio-3′-fluorophenyl]oxazoli-dine-2-ones from BAL resin immobilized 5-(S)-acetamidomethyl-3-[4′-acetylthio-3′-fluorophenyl]oxazoli-dine-2-one with methyl iodide (0.05 mL, 0.81 mmol) in N-methylpyrrolidine-2-one (1 mL). The synthesis was performed at r.t. overnight, and the crude cleaved product purified by TLC (eluent:. 10% methanol in dichloromethane). Yield 6.3 mg (52%). MS: 299 [M+H]+. 1H NMR.
Reaction SMILES: [CH2:1]1[C:3]2([C:9]3[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=3)[C:4]([NH:6][C:7](=O)[CH:2]12)=O.[CH2:16]([Mg]Br)[CH3:17].O>CCOCC>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:3]23[CH2:1][CH:2]2[CH:7]([CH2:16][CH3:17])[NH:6][CH2:4]3)=[CH:10][CH:11]=1
Reactant: O=C1NC(=O)C2(c3ccc(Cl)cc3)CC12
Reactant: CC[Mg]Br
Solvent: O
Solvent: CCOCC
Product: CCC1NCC2(c3ccc(Cl)cc3)CC12
Reaction time: 18 h

Procedure:
To 4.43 g of 1-(p-chlorophenyl)-1,2-cyclopropanedicarboximide in 100 ml of ether is added 16.4 ml of 2 M ethylmagnesium bromide. The mixture is allowed to stand at room temperature for 18 hours and then is combined with water. The ether solution is dried over sodium sulfate and evaporated to give 4.05 g of a pink semisolid. Crystallization from ether hexane gives 1-(p-chloropehnyl)-4-ethyl-4-hydroxy-3-azabicyclo[3.1.0]hexan-2-one as colorless crystals, m.p. 154°-157° C.
Reaction SMILES: C1(N=C=O)C=CC=CC=1.[CH:10]([P:12](=[O:17])([O:15][CH3:16])[O:13][CH3:14])=[CH2:11].[C:18]1([CH2:24][CH2:25][N+:26]([O-])=[O:27])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.N>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH2:24]([C:25]1[CH2:11][CH:10]([P:12](=[O:17])([O:15][CH3:16])[O:13][CH3:14])[O:27][N:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C=CP(=O)(OC)OC
Reactant: O=[N+]([O-])CCc1ccccc1
Agent: N
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O=C=Nc1ccccc1
Product: COP(=O)(OC)C1CC(Cc2ccccc2)=NO1
Reaction time: 8 h

Procedure:
13.5 ml (0.124 mol) of phenyl isocyanate, 9.5 g (0.07 mol) of dimethyl vinylphosphonate and 1 ml of triethylamine are introduced into 120 ml of toluene. A solution of 9.3 g (0.062 mol) of 2-phenylnitroethane and 1 ml of triethylamine dissolved in 150 ml of toluene is added dropwise in 5 hours, the mixture is stirred overnight and then for 30 minutes after addition of 30 ml of concentrated aqueous ammonia, precipitated diphenylurea is removed by filtration and washed with ethyl acetate, and the combined organic phases are extracted by shaking successively with water, 2 N hydrochloric acid and water, and are dried and concentrated. 13.9 g of reddish brown oil remain.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[CH:17]=[CH:18][N:19]=[CH:20][C:15]=2[C:14]2[C:9](=[CH:10][CH:11]=[N:12][C:13]=2[O:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:8]=1)(=O)=O.[CH2:28]([NH2:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])O.[Na+]>C1COCC1.C(OCC)(=O)C>[CH2:28]([NH:35][C:7]1[C:16]2[CH:17]=[CH:18][N:19]=[CH:20][C:15]=2[C:14]2[C:9](=[CH:10][CH:11]=[N:12][C:13]=2[O:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:8]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCCCOc1nccc2nc(OS(=O)(=O)C(F)(F)F)c3ccncc3c12
Reactant: NCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCOc1nccc2nc(NCc3ccccc3)c3ccncc3c12
Temperature: 80 °C

Procedure:
To a solution of 1-butoxypyrido[4,3-c]-1,6-naphthyridin-6-yl trifluoromethanesulfonate (127 mg, 0.253 mmol) in THF (2531 μl), benzylamine (111 μl, 1.013 mmol) was added. The reaction mixture was heated at 80° C. for 1 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate. Aqueous sodium hydrogen carbonate (saturated) was added, and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure to afford N-benzyl-1-butoxypyrido[4,3-c]-1,6-naphthyridin-6-amine as a brown oil. LRMS (APCI) calc'd for (C22H23N4O) [M+H]+, 359.2; found 359.1.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][NH:11][CH2:10][C:9]3[S:13][CH:14]=[CH:15][C:8]2=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([CH:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)#N.C(=O)([O-])[O-].[K+].[K+].[CH3:32][N:33](C)C=O>>[C:32]([C:15]1[C:8]2[CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:12][NH:11][CH2:10][C:9]=2[S:13][C:14]=1[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)#[N:33]
Reactant: N#CC(Br)c1ccccc1
Reactant: CN(C)C=O
Reactant: c1ccc(C2CNCc3sccc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: N#Cc1c(Cc2ccccc2)sc2c1C(c1ccccc1)CNC2
Yield: 67 %

Procedure:
A mixture of 4-phenyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine (6 g; 0.028 mole) (Example 3), o.cyanobenzyl bromide (5.9 g; 0.03 mole) and solid potassium carbonate (5.8 g; 0.042 mole) in dimethylformamide (100 ml) is heated at 70° C during 2 hours. After cooling, the precipitate is filtered and the solvent is evaporated off under reduced pressure. The residue is taken up into water and extracted with ether. The organic extracts are washed with water, dried over sodium sulfate, filtered through a silica bed and evaporated to dryness. The residue is recrystallized from cyclohexane: M.p. = 124° C (Yield: 67%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:20])[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:8][N:9]2NC=O)=[CH:4][C:3]=1[F:21].[C:22](=[O:25])([O-])[O-].[K+].[K+].CI.[CH3:30][N:31](C)C=O>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:20])[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:8][NH:9]2)=[C:4]([NH:31][CH2:30][CH:22]=[O:25])[C:3]=1[F:21]
Reactant: CCOC(=O)c1cn(NC=O)c2cc(Cl)c(F)cc2c1=O
Reactant: O=C([O-])[O-]
Reactant: CN(C)C=O
Agent: [K+]
Solvent: CI
Product: CCOC(=O)c1c[nH]c2cc(Cl)c(F)c(NCC=O)c2c1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 14.65 g (0.047 mole) of ethyl 7-chloro-6-fluoro-1-(formylamino)-1,4-dihydro-4-oxo-3-quinolinecarboxylate (Preparation 2), 12.9 g (0.094 mole) of potassium carbonate and 200 ml of dimethylformamide was stirred at 25° C. for 90 minutes. Methyl iodide (20.0 g, 0.141 mole) was then added and the reaction mixture was stirred at room temperature for 90 minutes. The dimethylformamide was removed in high vacuum at 50° C., and the residue was partitioned between 250 ml of water and 500 ml of chloroform. The chloroform layer was separated and dried over anhydrous magnesium sulfate. There was obtained from the chloroform solution upon concentration 13.8 g of ethyl 7-chloro-6-fluoro-1,4-dihydro-5-[(formyl)methylamino]-4-oxo-3-quinolinecarboxylate, m.p. 213°-216° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19]C3C=CC(C(OCC)=O)=CC=3)=[CH:14][C:13]=2[CH3:31])[CH2:11][CH2:10]1)[C:2]1C=CC=CC=1.[CH3:32][Si:33](C#C)([CH3:35])[CH3:34].[CH2:38](N(CC)CC)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:1]([O:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][Si:33]([CH3:35])([CH3:34])[CH3:32])=[CH:14][C:13]=2[CH3:31])[CH2:10][CH2:11]1)([CH3:2])[CH3:38]
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(C3(OCc4ccccc4)CC3)c(C)c2)cc1
Reactant: CCN(CC)CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: Cc1cc(C#C[Si](C)(C)C)ccc1C1(OC(C)C)CC1
Yield: 91 %

Procedure:
Using General Procedure D; 4-bromo-1-(1-isopropoxycyclopropyl)-2-methyl-benzene (Intermediate 79, 250.0 mg, 0.95 mmol) in triethylamine (8 mL) was treated with copper(I)iodide (19.0 mg, 0.10 mmol) and then sparged with argon for 5 minutes. Trimethylsilylacetylene (0.70 g, 7.1 mmols) was then added followed by dichlorobis-(triphenylphosphine)palladium(II) (70.0 mg, 0.1 mmol). The resulting reaction mixture was heated to 70° C. for 5d. The title compound (250.0 mg, 91%) was isolated by chromatography (0-3% EtOAc-hexanes).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:3]=1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(O)C>O>[Cl:8][C:6]1[CH:7]=[C:2]([N:20]2[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]2)[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:5]=1
Reactant: CN1CCNCC1
Reactant: Clc1cccc(-c2nc(Cl)cc(Cl)n2)c1
Solvent: O
Solvent: CCO
Product: CN1CCN(c2cc(Cl)nc(-c3cccc(Cl)c3)n2)CC1

Procedure:
a solution of 7.8 g. of 4,6-dichloro-2-(m-chlorophenyl)-pyrimidine and 6.0 g. of N-methylpiperazine in 35 ml. of absolute ethanol is refluxed for fifteen minutes. Pouring of the resulting solution into 700 ml. of water causes separation of a gummy material which solidifies on standing over a weekend. The crude product weighs 6.5 g. and recrystallization from n-heptane affords cotton-like crystals of 4-chloro-2-(3-chlorophenyl)-6-(4-methylpiperazin-1-yl)-pyrimidine, m.p. 93°-94°C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O.[C:24]1([NH:30][CH2:31][CH2:32][NH2:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O>[C:24]1([NH:30][CH2:31][CH2:32][NH:33][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCCNc1ccccc1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccccc1NCCNc1ccccc1

Procedure:
A mixture of 1-fluoro-2-nitrobenzene(15.5g, 110 mmol) and potassium carbonate (15.2 g, 110 mmol) was stirred and a mixture of N-methylpyrrolidone (20 ml) and N-phenylethylenediamine (15.0 g, 110 mmol) was added over 1 h at room temperature. The mixture was stirred for 1 h. Water (200 ml) was added crystals were filtered off and triturated with petroleum ether. Yield 14.7 g, 52%. M.p. 64-66° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:6]([CH3:8])([CH3:7])[CH2:5][C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:3]1.[CH:22](=O)[CH:23]([CH3:25])[CH3:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:22]([N:18]1[CH2:17][CH2:16][N:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:4]2[CH2:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:21])([CH3:1])[CH:3]=2)[CH2:20][CH2:19]1)[CH:23]([CH3:25])[CH3:24]
Reactant: CC1(C)C=C(c2ccccc2N2CCNCC2)CC1(C)C
Reactant: CC(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)CN1CCN(c2ccccc2C2=CC(C)(C)C(C)(C)C2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 18 %

Procedure:
To a solution of the 1-[2-(3,3,4,4-tetramethylcyclopent-1-enyl)phenyl]piperazine (20 mg, 0.0703 mmol) produced in Example (54d) in tetrahydrofuran (1 mL) were added isobutyraldehyde (6.6 mg, 0.0914 mmol), sodium triacetoxyborohydride (19.4 mg, 0.0914 mmol) and acetic acid (0.0076 mL, 0.134 mmol), followed by stirring for 4 hours at room temperature. After further adding isobutyraldehyde (6.6 mg, 0.0914 mmol), sodium triacetoxyborohydride (19.4 mg, 0.0914 mmol) and acetic acid (0.0076 mL, 0.134 mmol) to the mixture, stirring was continued for 3 hours at room temperature. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed three times with ethyl acetate. The obtained organic layers were concentrated and the resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 4.3 mg of 1-isobutyl-4-[2-(3,3,4,4-tetramethylcyclopent-1-enyl)phenyl]piperazine as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:15][CH:16]([Cl:20])[C:17](Cl)=O.Cl>>[Cl:15][CH:16]([Cl:20])[C:17]1[O:5][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([F:12])([F:13])[F:14])[C:2]=2[N:1]=1
Reactant: O=C(Cl)C(Cl)Cl
Reactant: Nc1c(C(=O)O)cccc1C(F)(F)F
Agent: Cl
Product: O=c1oc(C(Cl)Cl)nc2c(C(F)(F)F)cccc12
Temperature: 50 °C
Yield: 94 %

Procedure:
A mixture of 17.44 g of 2-amino-3-trifluoromethylbenzoic acid prepared by the process of J. Med. Chem., Vol. 16 (2) (1973), p. 101-106 and 34.63 g of dichloroacetyl chloride was progressively heated with stirring and at about 50° C., a hardening of the mass with rapid gas evolution of regular hydrogen chloride occured for one hour. Towards 100° C., one observed a fluidization of the reaction mixture, an intensification of hydrogen chloride evolution and an increase in the temperature to 127° C. The heating was continued until hydrogen chloride evolution ceased to obtain a brown solution which was cooled in an ice bath with stirring. The mixture was vacuum filtered and the product was empasted with ether, then with methanol and was washed with methanol to obtain 23.82 g of 2-dichloromethyl-8-trifluoromethyl-4H-3,1-benzoxazine-4-one melting at 179° C.
Reaction SMILES: Br[CH2:2][CH3:3].[CH:4]1[C:17]2[C:8](=[CH:9][C:10]3[C:15]([C:16]=2[CH2:18][NH:19][CH2:20][CH2:21][CH2:22][OH:23])=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:7]=[CH:6][CH:5]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH:14]1[C:15]2[C:10](=[CH:9][C:8]3[C:17]([C:16]=2[CH2:18][N:19]([CH2:2][CH3:3])[CH2:20][CH2:21][CH2:22][OH:23])=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:11]=[CH:12][CH:13]=1
Reactant: CCBr
Reactant: OCCCNCc1c2ccccc2cc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN(CCCO)Cc1c2ccccc2cc2ccccc12
Temperature: 75 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
Bromoethane (616 mg, 5.65 mmol) was dissolved in anhydrous acetonitrile and was added to the stirring mixture of compound 14a (500 mg, 1.9 mmol) and anhydrous K2CO3 (781 mg, 5.7 mmol). The mixture was then stirred overnight at 75° C. under a N2 atmosphere. After confirmation of the disappearance of 14a by TLC, the solution was concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (20 mL) and washed three times with aqueous sodium carbonate. The organic layer was separated, dried with anhydrous Na2SO4, filtered and concentrated under vacuum. Flash column chromatography of the residue gave 14b as a light yellow oil. Yield 82%; Rf=0.35 (3% MeOH/CHCl3); 1H NMR (CDCl3) δ 8.28 (m, 3H), 7.86 (d, 2H), 7.44 (m, 2H), 7.36 (m, 2H), 4.29 (s, 2H), 3.15 (t, 2H), 2.65 (q, 2H), 2.52 (t, 2H), 1.43 (q, 2H), 1.16 (t, 3H); 13C NMR (CDCl3) δ 131.2, 131.1, 129.3, 129.0, 127.6, 125.8, 124.8, 124.4, 63.4, 52.6, 50.5, 47.7, 28.1, 11.6. HRMS (FAB) m/z calcd. for C20H23NO (M+H)+ 294.1852; found 294.1859.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[F:8][C:9]1[C:14]([C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([C:26]4[CH:27]=[C:28]5[C:32](=[CH:33][CH:34]=4)[NH:31][N:30]=[CH:29]5)[CH:24]=3)[NH:19][CH:18]=2)=[O:16])=[C:13]([F:35])[CH:12]=[CH:11][C:10]=1[NH:36][S:37]([C:40]1[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:41]=1[F:47])(=[O:39])=[O:38]>O.C(OCC)(=O)C>[C:1]([N:31]1[C:32]2[C:28](=[CH:27][C:26]([C:23]3[CH:24]=[C:25]4[C:17]([C:15]([C:14]5[C:9]([F:8])=[C:10]([NH:36][S:37]([C:40]6[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:41]=6[F:47])(=[O:39])=[O:38])[CH:11]=[CH:12][C:13]=5[F:35])=[O:16])=[CH:18][NH:19][C:20]4=[N:21][CH:22]=3)=[CH:34][CH:33]=2)[CH:29]=[N:30]1)(=[O:3])[CH3:2]
Reactant: O=C(c1c(F)ccc(NS(=O)(=O)c2cc(F)ccc2F)c1F)c1c[nH]c2ncc(-c3ccc4[nH]ncc4c3)cc12
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)n1ncc2cc(-c3cnc4[nH]cc(C(=O)c5c(F)ccc(NS(=O)(=O)c6cc(F)ccc6F)c5F)c4c3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.9 %

Procedure:
Into a reaction flask, a mixture of acetic anhydride (12 mg, 0.11 mmol) and N-{2,4-difluoro-3-[5-(1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-2,5-difluoro-benzenesulfonamide (P-0002, 22 mg, 0.031 mmol) is stirred at room temperature overnight, then diluted with water and ethyl acetate. The organic layer is washed with saturated sodium bicarbonate, then brine and dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with methanol and dichloromethane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (P-0005, 3 mg, 20%). MS (ESI) [M+H+]+=607.8.